Nitrous oxide analgesia: reversal by naloxone and development of tolerance

The objective of this study was to characterize further the nature of nitrous oxide analgesia and to establish if tolerance to nitrous oxide occurs. Methods for studying the analgesic action of a gas are described. In mice, nitrous oxide is analgesic in the phenylquinone and acetic acid abdominal constriction tests. Aspirin and very high doses of alcohol are also active in these tests; however, only nitrous oxide-induced analgesia is antagonized by narcotic antagonists. These data indicate the mechanism of action of nitrous oxide analgesia differs from that of the other two drugs. Nitrous oxide produced a dose-related analgesic response in rats (ED50, 67%) as measured by the tail-flick method. Naloxone, 5 to 30 mg/kg, also antagonized nitrous oxide analgesia in rats. Lower doses of the antagonist were not effective. Tolerance developed to the effects of nitrous oxide in both rats and mice after prolonged exposure. These data lend support to the hypothesis that nitrous oxide and opiates have a significant pharmacologic resemblance and may ultimately produce similar molecular events in the brain leading to the relief of pain.     

Influence of naloxone on shock-induced freezing and analgesia.

Six experiments, with 196 male Holtzman rats, examined whether mild shock activates an opiate analgesia. Exps I–III explored whether naloxone potentiates shock-induced freezing by blocking an opiate analgesia. In Exp I, Ss treated with naloxone (3 or 50 mg/kg, sc) froze more following mild shock. Exp II revealed that both dose levels of the drug increase pain reactivity. Results of Exp III suggest that a naloxone-induced increase in pain reactivity accounts for the drug's effect on freezing. Exps IV–VI investigated the nature of the analgesia induced by mild shock. In Exp IV, mild shock induced a profound analgesia as measured by the tail-flick test. In Exp V, mild shock elicited a transient naloxone-insensitive analgesia that rapidly dissipated to reveal an analgesia that was reversed by a high dose of naloxone. This suggests that mild shock activates both the nonopiate and the opiate form of analgesia. Exp V also showed that a low dose of naloxone potentiated shock-induced analgesia. Exp VI revealed that this potentiated analgesia was attenuated by a high dose of naloxone. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inescapable shock-induced potentiation of morphine analgesia.

Exposure to various stressors potentiates nociceptive and nonnociceptive responses to morphine. These phenomena have received little study despite their seeming generality and importance for understanding analgesia and opiate action. The present experiments characterize inescapable shock (IS)-induced potentiation of morphine analgesia. Rats were exposed to IS, equal escapable shocks (ESs), or restraint (control). Potentiation of analgesia (tail-flick [TF] test and hotplate test) was observed only in rats given IS 24 or 48 hr earlier, in agreement with previously reported learned-helplessness effects. Finally, no change in tail temperature or motor function was found that could be inaccurately interpreted as analgesia. The relevance of these findings to stressor-induced enhancement of morphine analgesia and potential substrates of IS effects are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adjuncts to analgesia. Sedation and neuromuscular blockade

This article provides an overview of some of the current issues involved in sedation and anxiolysis in the intensive care unit. The problems involved in trying to monitor sedation levels are discussed, as are some of the newer options available for physiologic monitoring of the central nervous system. The problem of abnormal mental states in the intensive care unit and the range of antidepressant therapy now available are also covered. The importance of sleep deprivation and the properties of the neuromuscular blockers are also discussed.     

Acute reductions in serum testosterone levels by narcotics in the male rat: stereospecificity, blockade by naloxone and tolerance

The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The decline in testosterone levels reached a maximum 4 hours after the administration of morphine, at which time testosterone levels were reduced by more than 85% with respect to controls. The ability of a large number of narcotics to depress serum testosterone levels, 4 hours after their administration, was also examined. All narcotics depressed testosterone levels significantly and their potency relative to morphine was comparable to that observed in several other preparations, such as the guinea-pig ileum and mouse vas deferens. The testosterone-depleting effects of the narcotics appear to represent specific narcotic effects since the (-)-isomers of the narcotics were considerably more potent than the (+)-isomers, naloxone competitively inhibited the effects of morphine on testosterone levels and tolerance developed to the testosterone-depleting effects of these drugs. Acute treatment with morphine also lowered serum luteinizing hormone levels, and this reduction preceded the fall in testosterone levels by 1 to 2 hours.     

Naloxone blockade of morphine analgesia: a dose-effect study of duration and magnitude

The thioxanthene neuroleptic, cis-chlorprothixene, was approximately 200 times more potent than its transisomer as an inhibitor of the aggregation of human blood platelets induced by 5-hydroxytryptamine (5HT). Against the active uptake of 5HT by these cells, however, trans-chlorprothixene was twice as inhibitory as its cisisomer, and this inhibition was found to be competitive. It is suggested that 5HT adopts different conformations for binding to its two platelet receptors.     

Inescapable shock-induced potentiation of morphine analgesia in rats: Sites of action.

Inescapable shock (IS) enhances analgesia to systemic morphine (MOR) 24 hr later. IS activates serotonin neurons in the dorsal raphe nucleus (DRN), rendering them hyperexcitable. These studies tested whether IS potentiates the analgesic effect of MOR microinjected in the DRN, as predicted by this hypothesis. To test site specificity, the effect of previous IS was examined on MOR microinjected lateral to the DRN and into 2 other sites that support MOR analgesia, the nucleus raphe magnus (NRM) and spinal cord. Twenty-four hours after IS, potentiated analgesia was observed after 0.5 μg MOR microinjected into, but not lateral to, the DRN. Potentiated analgesia was also observed after NRM (1.0 μg) and spinal cord (3.0 μg) MOR microinjections. These data suggest that IS-induced excitability changes within the DRN synergize with opiates microinjected in other analgesia areas and that this potentiates the responses to opiates 24 hr after IS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ability of periaqueductal gray subdivisions and adjacent loci to elicit analgesia and ability of naloxone to reverse analgesia.

This study is an investigation of the effects of stimulation of regions within and adjacent to the periaqueductal gray (PAG) matter. Eighty-five rats were implanted with 1 monopolar stimulating electrode into 1 of 5 loci. Potency of analgesia was evaluated by relative increases in tailflick latencies after brain stimulation, and threshold current intensity was used to elicit analgesia. The ability of naloxone to reverse the stimulation-induced analgesia was also evaluated. Results replicate the previous finding of differential naloxone reversibility of ventral vs. dorsal PAG sites, but they do not support a regional distinction in the potency of analgesia induced. The results suggest that dorsal PAG sites are involved in a separate nonopiate pain-inhibitory system, whereas ventral sites are involved in an opiate system. These systems, however, do not respect the cytoarchitectural boundaries of the PAG because sites adjacent to the PAG elicit similar effects with a corresponding dorsal-ventral distinction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor

The aim of this study was to define from a morpho-structural point of view, using scanning electron microscopy, the features of various types of disposable latex gloves commonly used in Italian dental practice (Biogel D, Trend, Pagni, J&J, Latechnics, Pehasoft, Bantex). None of the brands examined was free from morphological flaws; however, while in some of these only slight depressions were found (Biogel D, Trend), in others (Latechnics, Bantex) there was a marked lack of homogeneity in the latex structure or real holes (Pehasoft). This study emphasizes the current difficulties faced by dentists in the search for safe working conditions.     

AT2-antagonist sensitive potentiation of angiotensin II-induced vasoconstrictions by blockade of nitric oxide synthesis in rat renal vasculature

1. Although the actions of angiotensin II (Ang II) on renal haemodynamics appear to be mediated by activation of the AT1 receptor subtype, AT2 binding sites have also been evidenced in the adult kidney vasculature. As NO is known to mask part of the renal effects of vasoconstrictor drugs, we queried whether the Ang II-induced vasoconstrictions could occur via multiple receptor subtypes during inhibition of NO synthesis. We explored the effect of AT1 and AT2 receptor (AT-R) antagonists on Ang II-induced pressure increases during NO synthase or soluble guanylyl cyclase inhibition in rat isolated kidneys perfused in the presence of indomethacin at constant flow in a single-pass circuit. 2. In the absence of NO blockade, the AT1-R antagonist L-158809 (500 nM) antagonized the Ang II-induced vasoconstrictions, while the AT2-R antagonist PD-123319 (500 nM) had no effect. 3. Perfusing kidneys in the presence of either NO synthase inhibitors, L-NAME (100 microM) or L-NOARG (1 mM), or soluble guanylyl cyclase inhibitor, LY-83583 (10 microM), significantly increased both molar pD2 (from 9.40+/-0.25 to 10.36+/-0.11) and Emax values (from 24.9+/-3.1 to 79.9+/-4.9 mmHg) of the concentration-response curve for Ang II-induced vasoconstriction. 4. In the presence of L-NAME, 500 nM L158809 abolished the Ang II-induced vasoconstrictions whatever the concentration tested. On the other hand, 500 nM PD-123319 reversed the left shift of the concentration-response curve for Ang II (molar pD2 value 9.72+/-0.13) leaving Emax value unaffected (91.3+/-7.6 mmHg). 5. In the presence of L-NAME, the potentiated vasoconstriction induced by 0.1 nM and the augmented vasoconstriction induced by 10 nM Ang II were fully inhibited in a concentration-dependent manner by L-158809 (0.05-500 nM). By contrast, PD-123319 (0.5-500 nM) did not affect the 10 nM Ang II-induced vasoconstriction and concentration-dependently decreased the 0.1 nM Ang II-induced vasoconstriction plateauing at 65% inhibition above 5 nM antagonist. 6. Similar to PD-123319, during NO blockade the AT2-R antagonist CGP-42112A at 5 nM decreased by 50% the 0.1 nM Ang II-induced vasoconstriction and at 500 nM had no effect on 10 nM Ang II-induced vasoconstriction. 7. In conclusion, the renal Ang II-induced vasoconstriction, which is antagonized only by AT1-R antagonist in the presence of endogenous NO, becomes sensitive to both AT1- and AT2-R antagonists during NO synthesis inhibition. While AT1-R antagonist inhibited both L-NAME-potentiated and -augmented components of Ang II-induced vasoconstriction, AT2-R antagonists inhibited only the L-NAME-potentiated component.     

Shock-induced analgesia on the formalin test: Effects of shock severity, naloxone, hypophysectomy, and associative variables.

In 5 experiments, 272 female Long-Evans rats were exposed to 3 shocks, spaced 20 sec apart, at 2 levels of severity: low (.75 sec, 1 mA) and high (3 sec, 4 mA). Both shock levels produced a similar suppression of the recuperative behavior elicited by an injection of formalin into the S's hindpaw. Naloxone fully reversed the analgesia produced by the low shock but only partially reversed the analgesia produced by the high shock. Hypophysectomy did not alter the level of analgesia. When the Ss were tested in a chamber different from the one in which they were shocked, both analgesias were totally reversed. However, imposing a delay between shock and analgesia testing did not reduce analgesia. In all experiments, the freezing response was monitored simultaneously with recuperative behavior. A parallel was found between analgesia and this defensive response, suggesting that an animal's endogenous analgesic systems may be activated along with its defensive motivational system. Results point to the critical nature of associative variables in the control of endogenous analgesic systems and suggest that shock severity is a determinant of analgesia's sensitivity to naloxone. (67 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat

OBJECTIVES: This study examined the relation of hysterectomy and oophorectomy to heart disease risk factors. METHODS: Data were collected and analyzed for 1150 women aged 50 through 89. RESULTS: Of these women, 21.8% reported hysterectomy with bilateral oophorectomy; 22.1%, hysterectomy with ovarian conservation. Compared with women without hysterectomy, oophorectomized women, especially those 20 or more years postmenopause, had increased lipids, lipoproteins, glucose, and insulin; blood pressures were increased among current estrogen users. Women with hysterectomies with ovarian conservation had similar or more favorable risk factors than nonhysterectomized women. CONCLUSIONS: Bilateral oophorectomy, but not hysterectomy, may have long-term negative consequences for heart disease risk factors not totally ameliorated by estrogen use.     

Blockade of apomorphine-induced aggression by morphine or neuroleptics: differential alteration by antimuscarinics and naloxone

Both morphine and the neuroleptics, haloperidol and oxyperomide, dose-dependently reduce the aggression in rats produced by 20 mg/kg of apomorphine, a dopamine receptor stimulant. The narcotics antagonist, naloxone, prevents this effect of morphine but not the effect of neuroleptics. Dexetimide, a centrally acting antimuscarnic drug, antagonizes the reduction in aggression produced by the neuroleptics, but does not affect morphine's action. The cholinergic agonist, pilocarpine, enhances this action of oxyperomide. These results suggest that a cholinergic component contributes to the anti-agression action of neuroleptics and demonstrates a difference in the mechanism of action between neuroleptics and morphine.     

Morphine analgesia: Enhancement by shock-associated cues.

Recent research has shown that rats exposed to repeated stress display enhanced morphine analgesia. Six experiments, with 218 male Sprague-Dawley rats, examined the possible contribution of classically conditioned analgesia to this effect. Drug-naive Ss exposed to 9 daily sessions of stress, each consisting of a single exposure to footshock, subsequently displayed enhanced analgesic responsiveness to morphine sulfate (5 mg/kg, sc) 1 and 10 days after stress. This enhancement was also observed in morphine-experienced Ss 1 and 8 days after stress. The effect of footshock stress on morphine analgesia was specific to the environment in which stress was administered. Conditioned analgesia was found under the same conditions that yielded enhanced morphine analgesia, and both this conditioned analgesia and the acute analgesia elicited by the footshock stressor were attenuated by naloxone (20 mg/kg). Data are consistent with the hypothesis that the enhanced morphine analgesia observed after repeated footshock stress reflects the contribution of an opioid-mediated, conditioned analgesia elicited by cues formerly paired with the stressor. (54 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inescapable shock-induced potentiation of morphine analgesia in rats: involvement of opioid, GABAergic, and serotonergic mechanisms in the dorsal raphe nucleus

Exposure of rats to inescapable shock (IS) potentiated the analgesic response to a low dose (1 mg/kg) of morphine 24 hr later. This effect was blocked by naltrexone (10 micrograms), diazepam (5 micrograms), or 8-hydroxy-2-(di-n-propylamine)-tetralin (8-OH-DPAT; 1 microgram) microinjected into the dorsal raphe nucleus (DRN) 15 min before IS. When microinjected into the DRN at the time of tail-flick testing, 8-OH-DPAT also effectively prevented this effect. Further, intra-DRN administration of a beta-carboline mimicked the effects of IS, because rats treated with methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (1 microgram) and simply restrained displayed potentiated morphine analgesia 24 hr later. These data suggest that this phenomenon shares mechanisms in common with other effects of IS at the level of the DRN.     

Morphine taste conditioning and analgesia: Assessing conditioned and novelty-induced analgesia.

In previous work showing a taste-elicited decrease in pain sensitivity (J. S. Miller, K. S. Kelly, J. L. Neisewander, D. F. McCoy, & M. T. Bardo, 1990), the rats (Rattus norvegicus) were always habituated to an inactive hot plate after each drug injection. The present report examined whether the analgesic response was a conditioned response to the taste or a response to the novelty of the hot plate resulting from morphine disrupting the habituation process. In 3 experiments, it was found that hot plate novelty was mainly responsible for the analgesic response. For example, increasing the number of conditioning trials did not enhance analgesia in morphine-treated rats. Rather, it attenuated analgesia in saline-treated controls (habituation). Also, rats given habituation in a drug-free state failed to show an analgesic response compared with controls. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin in the potentiation

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been studied in guinea-pigs. In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg-1 had no effect on capasaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg-1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg-1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vegal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B2 receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potentiating cough responses induced by capsaicin and citric acid in guinea-pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibitors.     

Differential effects of ibotenic acid lesions of the hippocampus and blockade of N-methyl-D-aspartate receptor-dependent long-term potentiation on contextual processing in rats

The contextual specificity of appetitive conditioned responding was examined in rats undergoing chronic intracerebroventricular infusion of 15 or 30 mM D-2-amino-5-phosphonopentanoic acid (D-AP5) or with excitotoxic hippocampal lesions. The magnitude of conditioned responding by control rats and rats infused with D-AP5 to a conditioned stimulus (CS) trained in Context A was attenuated when the same stimulus was presented in Context B. By contrast, hippocampal-lesioned rats displayed comparable levels of responding to the CS when presented in either Context A or B. Subsequent in vivo electrophysiological investigations showed that the D-AP5 concentrations were effective in blocking long-term potentiation (LTP) in the dentate gyrus. Results indicate that rats are capable of processing contextual information in the absence of N-methyl-D-aspartate (NMDA) receptor-dependent LTP and demonstrate an important dissociation between the effects of hippocampal lesions and the blockade of NMDA receptors in the hippocampus.     

Concurrent blockade of beta-adrenergic and muscarinic receptors suppresses synergistically long-term potentiation of population spikes in the rat hippocampal CA1 region

The muscarinic acetylcholine receptor antagonist scopolamine, but not the beta-adrenoceptor antagonist propranolol or atenolol, suppressed tetanus-induced long-term potentiation (LTP) of population spikes in the rat hippocampal CA1 region. When scopolamine was coapplied with propranolol or atenolol, a synergistic effect in preventing LTP generation was observed. On the other hand, the coapplication of scopolamine and atenolol failed to affect tetanus-induced LTP of field EPSP. These findings suggest that cooperative mechanisms via muscarinic and beta-adrenergic receptor activation might contribute to LTP induction in terms of the EPSP-spike potentiation, i.e., an increase in the excitability of hippocampal CA1 pyramidal cells after tetanic stimulation, but are independent of the tetanus-evoked potentiation of a synaptic component.